The hippocampus is a structure critical for learning and memory processes and is the site of a form of synaptic plasticity, called long-term potentiation (LTP), which represents a leading candidate for a cellular mechanism of learning. A number of steroid hormones have been shown to exert memory-enhancing effects in a variety of species and have thus been named memory-enhancing steroids. We hypothesize that the memory-enhancing steroids may produce their functional effects by modulating the physiological properties of hippocampal neurons. The experiments in this grant proposal are designed to investigate the actions of memory-enhancing steroids on hippocampal neurons, with particular focus on specific cellular and molecular mechanisms that may be involved in memory processes, such as hippocampal LTP. This will be accomplished at several mechanistic levels by using a combination of biochemical and electrophysiological approaches. Single-cell recordings will be used to assess the effects of memory-enhancing steroids on the membrane, synaptic, and pharmacological properties of CA1 neurons, including LTP, within the semi-intact functional circuitry of the hippocampal slice preparation (Specific Aim #1). The possibility of direct steroidal modulation of specific neurotransmitter receptors involved in hippocampal synaptic functioning will be tested with single-channel recordings (Specific Aim #2). Finally, the effects of memory-enhancing steroids on immediate early gene expression, a potential mechanism for coordinating long-term changes in synaptic plasticity, will be examined under conditions promoting LTP (Specific Aim #3). The findings from these studies should reveal important information on the mechanisms of steroidal modulation of neuronal excitability and synaptic functioning have possible therapeutic implications in clinical disorders involving memory deficits, such as Alzheimer's Disease.